Processes and intermediates for the preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains

ABSTRACT

Oxophthalazinyl acetic acids having aldose reductase inhibitory properties of the formula ##STR1## wherein Z is hydrogen or methyl, U is S, CH 2  or a covalent bond, and R 1 , R 3 , R 4 , R 5  and R 6  are as herein defined, are prepared by reacting an intermediate oxophthalazinyl acetic acid ester having a cyano or alkylamido group with an aniline derivative of the formula ##STR2## Processes for the preparation of the intermediate oxophthalazinyl acetic esters are disclosed.

REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. Ser. No. 59,899,filed June 9, 1987, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to the preparation of oxophthalazinylacetic acids having benzothiazole or other heterocyclic side chains.Such compounds function as aldose reductase inhibitors and are useful inthe treatment of certain chronic complications arising from diabetesmellitus, such as diabetes cataracts, retinopathy and neuropathy. Suchcompounds are disclosed in U.S. Ser. No. 263,577, filed Oct. 27, 1988,the disclosure of which is hereby incorporated herein by reference.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of acompound of the formula ##STR3## wherein R¹ is hydrogen or C₁ to C₄alkyl; R³ and R⁴ are the same or different and are hydrogen, fluoro,chloro, bromo, trifluoromethyl, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄alkylthio, C₁ -C₄ alkylsulfinyl, C₁ -C₄ alkylsulfonyl, or nitro, or R³and R⁴ taken together are C₁ -C₄ alkylenedoxy; R⁵ and R⁶ are the same ordifferent and are hydrogen, fluoro, chloro, bromo, trifluoromethyl, C₁-C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkylthio, C₁ -C₄ alkylsulfinyl, C₁ -C₄alkylsulfonyl, nitro, or benzo or R⁵ and R⁶ taken together are C₁ -C₄alkylenedoxy; Z is hydrogen or methyl; and U is S, CH₂ or a covalentbond, comprising reacting a compound of the formula ##STR4## wherein R¹,R³, R⁴ and Z are as defined above, W' is S, CH₂ or a covalent bond, andQ is --CN or ##STR5## wherein R² is C₁ -C₄ alkyl, or an acid additionsalt thereof with a compound of the formula ##STR6## wherein R⁵ and R⁶are defined above, or with an acid addition salt thereof, with theproviso that when neither one of said compounds of the formula VI andformula VII are in the form of its acid addition salt when it is addedto the other of said compounds, the reaction is conducted in thepresence of a strong acid; and, if desired, hydrolyzing a compound ofthe formula VIII wherein R¹ is other than hydrogen to the correspondingcompound of the formula VIII wherein R¹ is hydrogen. The compounds ofthe formula VI wherein Q is ##STR7## and all compounds of the formulaVII may form acid addition salts. Although, we do not wish to be boundby theory, we believe that the addition of a strong acid to theaforementioned reaction mixture results in the formation in situ of anacid addition salt of at least one (and possibly both) of the compoundsof the formula VI and formula VII and that the acid addition saltsubsequently reacts with the other compound. Thus, at least one of thereactants is an acid addition salt that is preformed or formed in situ.

The present invention also relates to the foregoing compounds of theformula VI, to processes for preparing intermediates useful in thepreparation of compounds of the formula VI, to intermediates useful inpreparing compounds of the formula VI, and to other processes whereinsuch intermediates are useful.

DETAILED DESCRIPTION OF THE INVENTION

The aforementioned compound of the formula VI wherein Q is --CN may beprepared by reacting a compound of the formula ##STR8## wherein R¹, R³and R⁴ are as defined for formula VIII, with a compound of the formulawherein X is chloro, bromo, --OSO₂ --(C₁ to C₄ alkyl), or --OSO₂ --arylwherein aryl is phenyl, naphthyl, substituted phenyl, or substitutednaphthyl, wherein the substituents on the substituted phenyl andsubstituted naphthyl groups are C₁ to C₄ alkyl, halogen or nitro; Z ishydrogen or methyl and W' is CH₂ or a covalent bond in the presence of asuitable base. The base should be of sufficient strength to catalyze thedesired nucleophilic displacement. Examples of suitable bases includealkali metal hydrides (e.g., sodium hydride), alkali metal carbonates(e.g., potassium carbonate) alkali metal hydroxides (e.g., sodiumhydroxide or potassium hydroxide), and alkali metal alkoxides (e.g.,potassium tert-butoxide or sodium methoxide). A suitable solvent forthis reaction is DMF (dimethylformamide). The reaction temperature ispreferably about 20° to about 100° C., more preferably about 40° C.

Alternatively, the compound of the formula VI wherein W' is a covalentbond, Z is hydrogen and Q is --CN may be prepared by reacting a compoundof the formula ##STR9## wherein Y is chloro or bromo; and R¹, R³ and R⁴are as defined for formula VIII, with an alkali metal cyanide oralkaline earth metal cyanide. Examples of suitable cyanides includesodium and potassium cyanide. Suitable solvents include C₁ -C₄ alcohols,C₁ -C₄ alkanones and polar aprotic solvents e.g., DMF. The reactiontemperature is preferably about 0° to about 40° C., more preferablyabout 20° C.

Compounds of the formula VI wherein W' is sulfur, Z is hydrogen and Q is--CN may be prepared by reacting a compound of the formula V wherein Yis chloro or bromo; and R¹, R³ and R⁴ are as defined for formula VIII,with an alkali metal or ammonium thiocyanate. Suitable solvents includeC₁ -C₄ alcohols, C₁ -C₄ alkanones and polar aprotic solvents, e.g., DMF.The reaction temperature is preferably about 0° to about 40° C., morepreferably about 20° C.

Compounds of the formula V where Y is chloro or bromo are, in turn,prepared from compounds of the formula V wherein Y is hydroxy byreaction with phosphorous trichloride or phosphorous tribromide at atemperature of about 0° to about 40° C., preferably about 20° C.

The aforementioned compound of the formula IV may be prepared byreacting a compound of the formula ##STR10## wherein R¹ is as definedabove, with NH₂ NH₂.

Alternatively, the compound of the formula II may be reacted with astrong acid (e.g., sulfuric acid or p-toluene sulfonic acid) to form acompound of the formula ##STR11## wherein R¹ is as defined for formulaVIII, and the compound of formula III may be reacted with NH₂ NH₂ toform a compound of formula IV.

Compounds of the formula V wherein Z is H, W is a covalent bond and Y ischloro or bromo are also useful in preparing compounds of the formula##STR12## wherein R¹, R³ and R⁴ are as defined above for formula VIII; Vis oxygen, sulfur or NH; and Het is a heterocyclic 5-membered ringhaving one nitrogen, oxygen or sulfur, two nitrogens one of which may bereplaced by oxygen or sulfur, or three nitrogens one of which may bereplaced by oxygen or sulfur, said ring substituted by one or twofluoro, chloro, C₁ -C₄ alkyl or phenyl or condensed with benzo, orsubstituted by one of pyridyl, furyl or thienyl, said phenyl or benzooptionally substituted by one of iodo or trifluoromethylthio, or one ortwo of fluoro, chloro, bromo, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄alkylthio, C₁ -C₄ alkylsulfinyl, C₁ -C₄ alkylsulfonyl, ortrifluoromethyl, and said pyridyl, furyl or thienyl optionallysubstituted in the 3-position by fluoro, chloro, bromo, C₁ -C₄ alkyl orC₁ -C₄ alkoxy; a heterocyclic 6-membered ring having one to threenitrogen atoms, or one or two nitrogen atoms and one oxygen or sulfur,and said ring substituted by one or two C₁ -C₄ alkyl or phenyl, orcondensed with benzo, or substituted by one of pyridyl, furyl orthienyl, said phenyl or benzo optionally substituted by one of iodo ortrifluoromethylthio, or one or two of fluoro, chloro, bromo, C₁ -C₄alkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkylthio, C₁ -C₄ alkylsulfinyl, C₁ -C₄alkylsulfonyl, or trifluoromethyl, and said pyridyl, furyl or thienyloptionally substituted in the 3-position by fluoro, chloro, C₁ -C₄ alkylor C₁ -C₄ alkoxy; oxazole or thiazole condensed with a 6-memberedaromatic group containing one or two nitrogen atoms or with thiophene orfurane, each optionally substituted by one of fluoro, chloro, bromo,trifluoromethyl, methylthio or methylsulfinyl; imidazolopyridine;naphthothiazole; or naphthoxazole. Such compounds are disclosed in U.S.Ser. No. 263,577, filed Oct. 27, 1988. The foregoing compounds of theformula X are prepared by reacting a compound of the formula V wherein Zis hydrogen, W is a covalent bond and X is chloro or bromo with anappropriate heterocycle containing an OH, SH, or NH₂ group in anaqueous, alcoholic, or polar aprotic solvent. Examples of suitablesolvents include ethanol and DMF. The reaction may be catalyzed by asuitable base. The base should be of sufficient strength to catalyze thedesired nucleophilic displacement. Examples of suitable bases includealkali metal hydrides (e.g., sodium hydride), alkali metal carbonates(e.g., potassium carbonate), alkali metal hydroxides (e.g., sodiumhydroxide or potassium hydroxide) and alkali metal alkoxides (e.g.,potassium tert-butoxide or sodium methoxide). The reaction temperatureis preferably about 30° to about 100° C., preferably about 40° C.

The processes of the present invention are illustrated by the followingreaction scheme: ##STR13##

A compound of the formula I is converted to a compound of the formula IIusing standard Reformatsky

reaction conditions with zinc or a zinc-copper couple or using a varietyof well-known modifications of the Reformatsky reaction (see, forexample Tetrahedron Letters, 2569 (1984)). Suitable solvents for theconversion of the compound of formula I to the compound of formula IIinclude aromatic hydrocarbons (e.g., benzene) and dialkyl ethers andcyclic ethers (e.g., tetrahydrofuran). The temperature is preferablymaintained at about 35° to about 100° C., more preferably, at reflux.

A compound of the formula II is converted to a compound of the formulaIII in the presence of a strong acid in a compatible solvent or withoutthe use of a solvent. When a solvent is used, it is preferred that thesolvent be a hydrocarbon solvent (e.g., benzene or toluene) and that theacid be an organic acid (e.g., p-toluenesulfonic acid). When suchconditions are used, the temperature should preferably be at least about90° C., more preferably, about 90° to about 100° C. The reaction mixturemay conveniently be maintained at the reflux temperature of the reactionmixture.

When it is desired to convert a compound of the formula II to a compoundof the formula III without using a solvent, it is preferred to use asthe acid sulfuric acid at a temperature of about 0° to about 30° C.,more preferably about 0° to about 20° C.

The conversion of a compound of the formula II or III to a compound ofthe formula IV may be accomplished with anhydrous or aqueous hydrazinein an alcoholic solvent (e.g., ethanol) at a temperature of about 20° toabout 80° C., preferably about 60° C. Thus, the temperature may be roomtemperature or the reflux temperature of the solvent.

A compound of the formula IV may be converted to a compound of theformula V where Y is OH as described in Tetrahedron, 531 (1964). Thereaction temperature is preferably about 20° to about 100° C., morepreferably about 30° to 40° C.

In order to prepare a compound of the formula VIII wherein R¹ is C₁ -C₄alkyl, a compound of the formula VI wherein Q is --CN may be reactedwith a preformed acid addition salt of a compound of the formula VII(e.g., a hydrochloride salt) or with an acid addition salt prepared insitu, for example, by the addition of a strong acid such as hydrochloricacid. In practice, it is convenient to use the preformed acid additionsalt. The solvent is preferably a C₁ to C₄ alkanol (e.g., ethanol) butmixtures of at least one molar equivalent of C₁ -C₄ alkanol with ahydrocarbon or halocarbon solvent may be used. Examples of hydrocarbonand halocarbon solvents include benzene and chloroform, respectively.The temperature is preferably at least about 60° C. The reaction mixtureis conveniently maintained at reflux temperature.

When the foregoing reaction is carried out in C₁ -C₄ alkanol solvents(e.g. ethanol), the resulting compound of the formula VIII wherein R¹ isC₁ -C₄ alkyl can be hydrolyzed in situ directly to the compound of theformula VIII wherein R¹ is H. The hydrolysis may be accomplished byadding an aqueous solution of a base such as sodium hydroxide orpotassium hydroxide. The temperature is preferably about 20° to about100° C., preferably about 60° C.

If a compound of the formula VIII is prepared in a solvent other than aC₁ -C₄ alkanol, the compound may be isolated, dissolved in a C₁ -C₄alkanol, and then hydrolyzed as described above.

The preparation of a compound of the formula VIII may also be carriedout by co-melting a mixture of a compound of the formula VI with apreformed acid addition salt of a compound of the formula VII (e.g., ahydrochloride salt) at a temperature between about 110° and about 180°C.

In another method, compound of the formula VIII may be prepared byreacting a compound of the formula VI wherein Q is ##STR14## wherein R²is C₁ -C₄ alkyl (hereinafter also referred to as a compound of theformula VIA) with a compound of the formula VII either as is or as inthe form of an acid addition salt (e.g. hydrochloride salt). Thereaction may be carried out in alcoholic, hydrocarbon or halocarbonsolvents. Examples of such solvents include ethanol, toluene andchloroform, respectively. The reaction temperature is preferably atleast about 60° C. The reaction mixture is conveniently maintained atreflux temperature. Alternatively the reaction may be carried out byco-melting a mixture of the compound of the formula VIA with a compoundof the formula VII at a temperature between about 110° and about 180° C.

The compound of the formula VIA may be prepared by reacting a compoundof the formula VI with a C₁ -C₄ alkanol in the presence of a mineralacid or organic acid. A preferred example of a mineral acid is gaseoushydrogen chloride. An example of an organic acid is p-toluene sulfonicacid. The reaction may be carried out at a temperature of about -5° C.up to about 40° C. If desired, the compound of the formula VIA may beprepared without adding an acid to the reaction mixture. In such a case,the reaction of the compound of the formula VIA and the compound of theformula VII should be conducted in the presence of a strong acid.

The reactions described above may be carried out at a pressure of about0.5 to about 2 atmospheres (preferably at a pressure of about 1atmosphere).

The compounds of formula VIII wherein R¹ is H and the pharmaceuticallyacceptable salts thereof are useful as inhibitors of the enzyme aldosereductase in the treatment of chronic complications of diabetes, such asdiabetic cataracts, retinopathy and neuropathy. The compounds may beadministered to a subject in need of treatment by a variety ofconventional routes of administration, including orally, parenterallyand topically. In general, these compounds will be administered orallyor parenterally at dosages between about 0.5 and 25 mg/kg. body weightof the subject to be treated per day, preferably from about 1.0 to 10mg/kg. However, some variation in dosage will necessarily occurdepending on the condition of the subject being treated.

The following non-limiting Examples are illustrative of the presentinvention. All melting points are uncorrected.

EXAMPLE 1 Ethyl-1,3-dihydro-1-hydroxy-3-oxo-1-isobenzofuran acetate

Procedure A

To a refluxing slurry of zinc dust (37.0) in benzene (250 ml) was addeda portion (15 ml) of a solution of ethyl bromoacetate (8.35 g) andphthalic anhydride (7.4 g) in benzene (250 ml). Following an exothermicreaction during this addition, the remaining portion of the benzenesolution was added and the refluxing continued for 8 hours. The reactionmixture was cooled to room temperature and was then poured onto aqueoussulfuric acid (100 ml, 10%) and the organic layer was collected. Thisorganic layer was sequentially washed with water (2×50 ml), aqueoussodium bicarbonate (25 ml, 10% by weight) and finally with water (25ml). The washed organic extract was dried and evaporated. The resultingcrude product was purified by chromatography (yield: 12.84 g; ¹HNMR(CDCl₃, 60 MHz); 1.25(t, J-8 Hz, 3H), 3.15 (s, 2H), 4.2 (9, J=8 Hz,2H), 6.25 (broad, 1H), 7.6 (M, 4H)).

Procedure B

To a refluxing suspension of zinc-copper couple (31.0 g) intetrahydrofuran (50 ml) was gradually added a solution of phthalicanhydride (29.6 g) and ethyl bromoacetate (13.1 g) in tetrahydrofuran(150 ml). The reaction mixture was refluxed for 2 hours and it was thencooled and filtered. The filtrate was added to aqueous HCl (200 ml, 10%by volume) and then extracted with ethyl acetate (3×5 ml). The ethylacetate layer was washed with water (2×50 ml) and evaporated to a clearcolorless oil (yield: 18.2 g; ¹ HNMR as in Procedure A).

EXAMPLE 2 t-Butyl-1,3-dihydro-1-hydroxy-3-oxo-1-isobenzofuran acetate

Starting from phthalic anhydride (14.81 g), t-butyl bromoacetate (29.25g), zinc-copper couple (15.0 G) and tetrahydrofuran (100 ml) and usingthe method of Procedure B, the title product was obtained (yield; 24.0g). This product was further purified by chromatography (¹ HNMR (CDCl,250 MHz), 1.90 (s, 9H), 4.0 (s, 2H), 6.7-7.2 (m, 4H)).

EXAMPLE 3 (Z)-3-Ethoxycarbonylmethylidenaphthalide,

Ethyl-1,3-dihydro-3-oxo-1-isobenzofuran acetate (2.36 g) was dissolvedin concentrated sulfuric acid (5 ml) and allowed to stand at roomtemperature for 5 minutes. It was then slowly poured onto ice-water (50ml) and the resulting white precipitate was collected, washed with water(3×25 ml) and then air-dried (yield: 2.08 g; See J. Org. Chem., 31,4077, (1966).

EXAMPLE 4 Ethyl-4-oxo-3H-phthalazin-1-yl-acetate

To a solution of ethyl-1,3-dihydro-3-oxo-1-isobenzofuran acetate (4.72g) in ethanol (20 ml) was added hydrazine (1.28 g) all in one portion.The resulting white precipitate was collected, washed with aqueous HCl(20 ml, 10% by volume) and then with water. The solid was air-dried toobtain the title compound (See U.S. Pat. No. 4,251,528).

EXAMPLE 5 t-Butyl-4-oxo-3H-phthalazin-1-yl-acetate

To a solution of t-butyl-1,3-dihydro-1-hydroxy-3-oxo-1-isobenzofuranacetate (7.92 g) in ethanol (200 ml) was added hydrazine hydrate (5.0ml, 85% by weight) and then refluxed for 1 hour. The precipitated whitesolid was collected, washed with water (2×25 ml) and then air-dried(yield: 5.30 g; m.p. 164°-166° C.).

EXAMPLE 6 Methyl-3-cyanomethyl-4-oxo-3-H-phthalazin-1-ylacetateProcedure A

To a mixture of methyl-4-oxo-3-H-phthalazin-1-ylacetate (5.45 g) indimethylformamide (25 ml) was added dry potassium t-butoxide (2.95 g)all in one portion. To the resulting dark green solution was graduallyadded chloroacetonitrile (1.89 g). The reaction mixture was stirred for30 minutes and was then poured onto ice water (100 ml). Sufficient 10%HCl (by volume) was added to adjust the pH of the resulting mixture toabout 4.0 and the precipitated off-white solid was collected andair-dried (yield: 5.74 g; m.p. 118°-119° C.).

Procedure B

Procedure A was repeated as above except that chloroacetonitrile wasreplaced by bromoacetonitrile (3.0 g). The title product was obtained in4.93 g yield with the same melting point as the product of Procedure A.

Procedure C

Procedure A was repeated on twice the scale but chloroacetonitrile wasreplaced by cyanomethyl benzenesulfonate (10.90 g). The title productwas obtained in 10.98 g yield.

EXAMPLE 7 Ethyl-3-cyanomethyl-4-oxo-3-H-phthalazin-1-ylacetate ProcedureA

To a solution of ethyl-4-oxo-3-H-phthalazin-1-yl acetate (11.31 g) anddry potassium t-butoxide (5.9 g) in dimethylformamide (50 ml) was addedchloroacetonitrile (3.78 g) and the solution was stirred for 30 minutes.This solution was poured onto ice water (300 ml); sufficient 10% HCl wasadded to adjust the pH of the resulting mixture to about 4.0 and theprecipitated solid was collected and air-dried (yield: 11.81 g; m.p.113°-114° C.).

Procedure B

Chloroacetonitrile (3.0 ml) was added to a solution of ethyl4-oxo-3H-phthalazin-1-ylacetate (10.0 g) in dimethylformamide (100 ml)containing anhydrous potassium carbonate (9.0 g) and the mixture wasstirred overnight. It was then poured onto ice-water (500 ml);sufficient 10% HCl was added to adjust the pH to about 4.0 and theprecipitated solid was obtained upon air drying (yield: 9.7 g; m.p.113°-114° C.).

Procedure C

A mixture of ethyl-4-oxo-3H-phthalazin-1-ylacetate (5.0 g), potassiumcarbonate (4.5 g), acetone (100 ml) and chloroacetonitrile (2.0 ml) wasrefluxed overnight. The reaction mixture was then worked-up as inProcedure B (yield: 4.1 g).

Procedure D

To an ice-cold solution ofethyl-3-bromomethyl-4-oxo-3-H-phthalazin-1-ylacetate (2.43 g) in acetone(3.5 ml) was added dropwise a solution of potassium cyanide (0.49 g) andpotassium iodide (2 mg) in water (3.5 ml). The reaction mixture wasstirred for 2 hours and it was then poured onto ice water (200 ml). Theprecipitated solid was purified by chromatography on silica gel, elutingwith 95% CH₂ Cl₂ -5% ethyl acetate (percents by volume) to obtain thetitle compound (yield: 1.54 g).

EXAMPLE 8 Ethyl-3-cyanoethyl-4-oxo-3-H-phthalazin-1-ylacetate

To a solution of ethyl-4-oxo-3-H-phthalazin-1-ylacetate (10.91 g) anddry potassium t-butoxide (5.90 g) in dimethylformamide (50 ml) was added3-chloropropionitrile (4.92 g) and the resulting solution was stirredfor 30 minutes. The solution was then poured onto ice-water (300 ml);sufficient 10% HCl was added to adjust the pH of the resulting mixtureto about 4.0 and the precipitated solid was collected and crystallizedfrom methanol (yield: 7.64 g; m.p. 125°-126° C.).

EXAMPLE 9 Ethyl-3-hydroxymethyl-4-oxo-3-H-phthalazin-1-ylacetate

A mixture of ethyl-4-oxo-3-H-phthalazin-1-ylacetate (23.42 g), ethanol(200 ml) and aqueous formaldehyde (37% concentration, 100 ml) wasrefluxed for 40 hours. This solution was concentrated to 100 ml and wasthen poured onto ice water (750 ml). The precipitated solid wascollected and air-dried (yield: 17.1 g; m.p. 113°-114° C.).

EXAMPLE 10 Methyl-3-hydroxymethyl-4-oxo-3-H-phthalazin-1-ylacetate

A mixture of methyl-4-oxo-3-H-phthalazin-1-ylacetate (2.18 g), methanol(50 ml) and aqueous formaldehyde (37% concentration, 10 ml) was refluxedfor 40 hours. The reaction mixture was cooled to room temperature andthen poured onto water (50 ml). The resulting solid was collected andcrystallized from methanol (yield: 0.5 g; m.p. 154°-155° C.).

EXAMPLE 11 Ethyl-3-bromomethyl-4-oxo-3-H-phthalazin-1-ylacetate

A solution of ethyl-3-hydroxymethyl-4-oxo-3-H-phthalazin-1-ylacetate(13.1 g), phosphorous tribromide (13.5 g) and anhydrous ether (250 ml)was stirred overnight at room temperature. It was then poured onto water(200 ml). The organic layer was collected, washed again with water(3×100 ml) and then dried over anhydrous sodium sulfate. The driedorganic extract was evaporated to dryness and the resulting crude solidwas purified by chromatography on silica gel, eluting with 95% CH₂ Cl₂₋5% ethyl acetate (percents by volume) to obtain the title compound(yield: 9.8 g; m.p. 96° C.).

EXAMPLE 12 Methyl-3-bromomethyl-4-oxo-3-H-phthalazin-1-ylacetate

A solution of methyl-3-hydroxymethyl-4-oxo-phthalazin-1-ylacetate (0.49g), phosphorous tribromide (0.54 g) and methylene chloride (10 ml) wasstirred at room temperature for 2 hours. The solution was poured ontoice-water (5 ml) and the separated methylene chloride layer wascollected, dried and evaporated to obtain a light yellow solid (yield:0.43 g; m.p. 98°-104° C.).

EXAMPLE 13 Ethyl-3-Chloromethyl-4-oxo-3-H-phthalazin-1-ylacetate

A solution of ethyl-3-hydroxymethyl-4-oxo-3-H-phthalazin-1-ylacetate(1.31 g) and methanesulfonyl chloride (0.69 g) in methylene chloride (10ml) containing pyridine (0.8 ml) was stirred at room temperatureovernight. Upon evaporation of methylene chloride and purification ofthe residue by chromatography on silica gel, eluting with a mixture of achloroform and ethyl acetate (9:1), the title product was obtained(yield: 0.51 g; m.p. 99°-100° C.).

Alternatively, follow the procedure in Example 11, but substitutephosphorous trichloride for phosphorous tribromide, to obtain the titlecompound.

EXAMPLE 14Ethyl-3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3-H-phthalazin-1-ylacetateProcedure A

A mixture of ethyl 3-cyanomethyl-4-oxo-phthalazin-1-ylacetate (2.71 g),2-amino-4-trifluoromethyl-thiophenol hydrochloride (2.40 g) and ethanol(20 ml) was refluxed for 8 hours. The heavy precipitate obtained uponcooling was filtered and the collected solid was air-dried to obtain thetitle compound (yield: 4.3 g; m.p. 136° C.).

Procedure B

A mixture of ethyl 3-cyanomethyl-4-oxo-phthalazin-1-ylacetate (0.27 g)and 2-amino-4-trifluoromethylthiophenol hydrochloride (0.23 g) washeated to a melt at 180° C. for 10 minutes. The mobile liquid was cooledand then suspended in water. Filtration of the mixture gave the titlecompound in 75% yield.

EXAMPLE 15Ethyl-3-(5,7-difluorobenzothiazol-2-ylmethyl)-4-oxo-3-H-phthalazin-1-ylacetate

A mixture of ethyl-3-cyanomethyl-4-oxo-phthalazin-1-ylacetate (1.29 g),2-amino-4,6-difluoro-thiophenol hydrochloride (0.98 g) and ethanol (20ml) was refluxed for 6 hours. Upon cooling, the title compoundprecipitated out as a pale yellow solid (yield: 1.62 g; m.p. 115°-117°C.).

EXAMPLE 163-(5-Trifluoromethylbenzothiazole-2-ylmethyl)-4-oxo-3-H-phthalazin-1-ylaceticacid Procedure A

A mixture ofethyl-3-(5-trifluoromethylbenzothiazole-2-ylmethyl-4-oxo-3-H-phthalazin-1-ylacetate(5.0 g), methanol (60 ml), tetrahydrofuran (30 ml) and 10% aqueouspotassium hydroxide (20 ml) was stirred for 10 minutes at roomtemperature. The solution was concentrated to a volume of 20 ml and wasthen diluted with water (50 ml). The resulting solution was acidified topH about 4.0 by addition of sufficient 10% HCl. The precipitatedoff-white solid was collected and air-dried (yield: 4.8 g; m.p.197°-198° C.).

Procedure B

A mixture of ethyl-3-cyanomethyl-4-oxo-phthalazin-1-ylacetate (2.71 g),2-amino-4-trifluoromethyl-thiophenol hydrochloride (2.40 g) and ethanol(20 ml) was refluxed overnight. The reaction mixture was cooled to 40°C. and to it was added tetrahydrofuran (10 ml) and 5% aqueous potassiumhydroxide (10 ml). The mixture was stirred for 1 hour at roomtemperature and the solvents were removed by evaporation. The residuewas diluted with water (50 ml) and the resulting solution was extractedwith ether (20 ml). The basic aqueous layer was collected and acidifiedto pH of about 4.0 by addition of sufficient 10% HCl. The precipitatedsolid was collected and air-dried (yield: 3.68 g; m.p. 197°-198° C.).

EXAMPLE 173-(5,7-Difluorobenzothiazole-2-ylmethyl)-4-oxo-3-H-phthalazin-1-ylaceticacid

Ethyl3-(5,7-difluorobenzothiazol-2-ylmethyl)-4-oxo-3-H-phthalazin-1-ylacetate(1.0 g) was hydrolyzed according to the method of Example 16, ProcedureA, to obtain the title compound (m.p. 178° C.).

EXAMPLE 183-(5-Trifluoromethylbenzothiazole-2-ylethyl)-4-oxo-3-H-phthalazin-1-ylaceticacid

A mixture of ethyl-3-cyanoethyl-4-oxo-3-H-phthalazin-1-ylacetate (2.71g), 2-amino-4-trifluoromethyl-thiophenol hydrochloride (2.29 g) andethanol (20 ml) was refluxed overnight. The crude product obtained uponevaporation of ethanol was purified by chromatography on silica gel,eluting with a mixture of hexane and tetrahydrofuran (4:1). The whitesolid obtained (0.3 g) was used directly in the next step whichconsisted of dissolving the compound in ethanol (20 ml) containing 5%aqueous KOH (2 ml) and stirring at room temperature for 2 hours. Theethanol was evaporated, the residue was diluted with water (10 ml),extracted with ether (2×10 ml) and the aqueous extract acidified to pH2.0. The precipitated solid was collected and then crystallized fromethanol (yield: 0.12 g; m.p. 184°-185° C.).

EXAMPLE 19 Ethyl-3-(ethyl acetimidate)-4-oxo-3H-phthalazin-1-ylacetate,hydrochloride

Dry hydrogen chloride gas was passed for 5 minutes into a solution of3-cyanomethyl-4-oxo-phthalazin-1-ylacetate (27.1 g) in drytetrahydrofuran (200 ml) and absolute ethanol (5.9 ml). The precipitateformed upon letting the reaction stand at room temperature overnight wasfiltered off to obtain the desired product (13.05 g, m.p. 208°-210° C.).

EXAMPLE 20Ethyl-3-(5-trifluoromethylbenzothiazole-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetate

A mixture of ethyl-3-ethyl acetimidate)-4-oxo-3H-phthalazin-1-ylacetatehydrochloride (0.35 g) and 2-amino-5-trifluoromethyl thiophenolhydrochloride (0.23 g) in toluene (20 ml) was refluxed for 16 hours. Theprecipitate obtained upon cooling was crystallized from ethanol toobtain the product (m.p. 136° C.).

EXAMPLE 21 Ethyl-3-thiocyanatomethyl-4-oxo-3-H-phthalazin-1-ylacetate

Following the method of Procedure D of Example 7, but replacingpotassium cyanide by potassium thiocyanate, prepare the title compound.

We claim:
 1. A compound of the formula ##STR15## wherein R¹ is hydrogenor C₁ to C₄ alkyl; and R³ and R⁴ are the same or different and arehydrogen, fluoro, chloro, bromo, trifluoromethyl, C₁ -C₄ alkyl, C₁ -C₄alkoxy, C₁ -C₄ alkylthio, C₁ -C₄ alkylsulfinyl, C₁ -C₄ alkylsulfonyl, ornitro, or R³ and R⁴ taken together are C₁ -C₄ alkylenedioxy Z ishydrogen or methyl; W' is S, CH₂ or a covalent bond; and Y is hydroxy,chloro, bromo, cyano or ##STR16## wherein R² is C₁ -C₄ alkyl.
 2. Acompound according to claim 1, wherein R¹ is methyl or ethyl, R³ and R⁴are hydrogen, W' is a covalent bond or CH₂, and Y is CN.
 3. A compoundaccording to claim 2, wherein R¹ is methyl or ethyl, W' is a covalentbond and Z is hydrogen; or R¹ is ethyl, W' is CH₂ and Z is hydrogen. 4.A compound according to claim 1, wherein R¹ is methyl or ethyl, R³ andR⁴ are hydrogen, and Y is chloro or bromo.
 5. A compound according toclaim 4, wherein Z is hydrogen.
 6. A compound according to claim 1,wherein R¹ is methyl or ethyl, R³ and R⁴ are hydrogen and Y is hydroxy.7. A compound according to claim 6, wherein Z is hydrogen.
 8. A compoundaccording to claim 1, wherein Y is ##STR17## wherein R² is C₁ -C₄ alkyl.9. A compound according to claim 1, wherein R³ and R⁴ are hydrogen and Yis ##STR18## wherein R² is ethyl.